Pressurized metered dose inhaler (pMDI) can make the inhaled pharmaceuticals topically and rapidly present the activity of the medicine, and has lower systemic adverse reaction when compared with an oral drug. The pMDI and dry powder inhaler (DPI) are the most general administrations for asthma or chronic obstructive pulmonary disease (COPD), which are used to administer the composition being one selected from a group consisting of a corticosteroid drug, a beta-2 agonist, an anticholinergics and a combination thereof.
Since 1995, Company 3M developed a product of pMDI with chlorofluorocarbons (CFC) as a propellant, and the product has become most popular administration for treating asthma or COPD. Compared with the oral drug, the pMDI may present activity more rapidly and provide lower systemic adverse reaction of the medicine. Typical components for treating such diseases include a corticosteroid drug, a beta-2 agonist, an anticholinergics, or a pharmaceutical composition being a dose inhaler and consisting of the mentioned drugs.
In the 1970s, it is found that the propellant of CFC may result in environmental protection problems in destroying ozonosphere, and thus the CFC is confronted by the situation of global restriction. In the end of 1980s, a substitute product of the DPI was developed, but the substitute product can not completely replace the pMDI with the CFC propellant all along, since the product tends to suffer moisture and the patient needs enough speed of inhaling when using the product to be efficiently administered. Until now, Company Riker of 3M firstly develops a substitute propellant for replacing the CFC propellant, i.e. the propellant of hydrofluoroalkanes (HFA), which includes 1,1,1,2-tetrafluoroethane (HFA 134a, HFC 134a) or 1,1,1,2,3,3,3-heptafluoro-n-propane (HFC 227ea, HFC 227, HFA227). However, because there are some problems, such as techniques of preparation and drug safety, to be overcome, the first product of the formulation of HFA MDI did not enter into the market until 1996, and was booming in 2004, which results in the complete restriction on producing the CFC MDI after 2010.
In the U.S. Pat. Nos. 5,225,183, 5,439,670, 5,695,743, 5,766,573, 5,836,299 and 6,352,684 owned by Company Riker/3M, the patented formulation including HFA 134a has been disclosed. The formulation includes components of β-2-adrenergic agonists including such as salbutamol, corticosteroid such as beclomethasone dipropionate, adrenergic components, choline and anti-histamine or anti-inflammatory drugs, and uses 1-50% ethanol compound as a solubilizer, and the surfactant, which may be the derivatives such as oleic acid, polyethylene glycol 400(PEG 400) or Span, is added with a weight ratio less than 5%. In the U.S. Pat. No. 6,743,413, HFA 134a and micronized drugs are used as main components without other excipients. The U.S. Pat. No. 5,776,432 discloses that HFA 134a, HFA 227, or a combination thereof is used as the propellant, and 2%-12% ethanol is used as the solubilizer of the main drug component, beclomethasone 17, 21 dipropionate, without any surfactant.
The U.S. Pat. No. 5,474,759 owned by Company Schering discloses that HFA 227 is used as the propellant, and propylene glycol diester with a long chain is used as the surfactant, wherein the main components thereof include compounds such as albuterol, albuterol sulfate, beclomethasone dipropionate, or mometasone furoate.
In the U.S. Pat. Nos. 5,653,962, 5,658,549 and 5,744,123 owned by Company GSK, the patented formulation including HFA has been disclosed. The formulation includes main components such as salmeterol, salbutamol and fluticasone propionate, but does not have co-solvent, and uses the surfactant less than 0.001%. The subsequent patents thereof relate to the modification of drug delivery uniformity. The U.S. Pat. Nos. 6,315,173 and 6,510,969 relate to the improvement of the sprinkle-nozzle. The U.S. Pat. No. 6,479,035 uses Fluticasone and 7-20% alcohol as the solubilizer, and uses 0.5-3% glycerol or PEG as the surfactant. In the U.S. Pat. Nos. 5,736,124, 5,817,293, 5,916,540, 5,922,306, 6,333,023, 6,200,549 and 6,222,339, the main component of formoterol has been disclosed, and 0.01-5% ethanol is adopted. The U.S. Pat. Nos. 6,303,103 and 6,238,647 disclose that salmeterol and anti-cholinergics are incorporated, and the excipient used thereby is less than 0.0001%. The U.S. Pat. No. 6,013,245 relates to beclomethasone and salbutamol, uses HFA 227 and does not use the surfactant. The U.S. Pat. No. 5,833,950 discloses beclomethasone, and uses HFA and the excipient less than 0.0001%.
Company Aeropharm has disclosed a patented formulation including HFA. The U.S. Pat. No. 5,891,419 discloses flunisolide with an addition of 0.5%-2% ethanol only. The U.S. Pat. No. 5,891,420 discloses triamcinolone acetonide with an addition of 1%-3% ethanol. The U.S. Pat. No. 6,458,338 relates to a metered dose formulation with amino acid as the stabilizer. In the U.S. Pat. Nos. 6,447,750, 6,540,982, 6,540,983, 6,548,049 and 6,645,468, a metered dose formulation of a main component of a drug treating diabetes has been disclosed. The U.S. Pat. No. 6,464,959 discloses a metered dose formulation of a main component of a drug treating diabetes, which is incorporated with amino acid as the stabilizer.
The U.S. Pat. No. 6,004,537 owned by Company Baker Norton (now TEVA) discloses that HFA is used as the propellant, and uses 10%-40% (w/w) ethanol as the solubilizer to dissolve the main components of Budesonide and Formoterol.
The U.S. Pat. No. 6,123,924 owned by Fisons discloses main components such as β2-receptor agonist: fenoterol hydrobromide, procaterol hydrochloride, salbutamol sulphate, terbutaline sulphate, anabolic steroid or steroid components; beclomethasone dipropionate, fluticasone propionate, tipredane, anti-histamine, anti-inflammation or acetyl-β-methylcholine bromide; cholinergic components: pentamidine isoethionate, tipredanene, docromil sodium, sodium cromoglycate, clemastine, budesonide and so on, which are distributed in HFA, and uses of polyvinylpyrrolidone (PVP) of 0.0000˜10% w/w as the suspending agent and PEG 400-3000 as the lubricating agent.
The TW Patent Application No. 200303767 owned by Company Chiesi discloses formoterol superfine formulation, which includes 0.003-0.192% w/v of (R,R)-(±)-formoterol fumarate, wherein the combination technique of pressurized metered inhaler formulation is used and 10˜20% ethanol and HCl are used to adjust pH value. It is emphasized that the ratio of particles equal to or less than 1.1 micrometer is larger than or equal to 30%. In the U.S. Pat. No. 7,223,381, the formulation is consisting of Budesonide, HFA propellant, and co-solvents of 13% ethanol and 0.2˜2% glycerol.
The U.S. Pat. No. 6,638,495 owned by Company Nektar relates to a formulation combination technique where the phospholipid is used as the excipient to form a microstructure and materials having biological activities are distributed in the pressurized metered inhaler.
The U.S. Pat. No. 6,932,962 owned by Company AstraZeneca relates to HFA atomization dose including fatty acid or a salt thereof, bile salts, phospholipid or alkyl glycosides as the surfactant, wherein the amount of the ethanol used thereby can be 5-20%.
The U.S. Pat. No. 7,481,995 owned by University College Cardiff Consultants Limited relates to a HFA MDI formulation technique which uses amino acid as the suspending excipient.
When observing the mentioned prior arts based on the pressurized metered dose inhaler prescription, in addition to the medicine and HFA gas, the techniques can be classified according to using conditions of the ethanol as follows.
1). Without any additives, as represented by Company GSK, which provides the medicine completely presented by a suspending solution mode, while such medicine has a problem that it is more difficult to make the administration uniform.
2). Without the use of ethanol and a simple use of an excipient, such as PVP or propanediol bischloroacetate.
3). Large amount of ethanol (more than 10%), which would completely dissolve the medicine, and other excipients may be added or not. In this case, the advantage is good uniformity of the administration, and the disadvantage are possibly worse stability of the medicine and the rare delicacy of alcohol that has bad acceptance for patients.
4). Medium-low amount of ethanol (about 1% to 10%) collocated with other excipients, in which the medicine is in a condition of partially being dissolved and partially without being dissolved. It has bigger effect on the stability of the formula that the particle diameter of the medicine would be caused to change with passing of the preserving time.
5). Extreme-low amount of ethanol (about 0.2% to 2%), such as the formula of Company Valois. In this case, the advantage is the better stability of the medicine since it is in a suspending solution station without being dissolved, while the disadvantage is the bad uniformity of the administration and thus the assistance of other excipients may be needed. Moreover, it may have more difficulty in the manufacturing process.
Although Valois SAS has published the formula about Budesonide HFA MDI, which uses 0.1-5% of PEG 300 and 0.2-2% of ethanol (referring to Indian Journal of Pharmaceutical Science, Vol. 69, No. 5, P. 722-724, September-October 2007). However, in order to reduce the absorption of the container with the drug and increase the uniformity of the administration, the mentioned formula needs a use of a special surface-anodized container, such as a standard anodized aluminum canister, to be filled therewith. When it is used in an scale-up production or a general container, such as an aluminum canister, some problems about quality would be generated. Accordingly, when actually mass producing the mentioned formula in pharmaceutical industry, even though the formula components are the same, the differences of quality would still be resulted from different mixture orders of components and different ways and equipments of filling. The examples of the differences of quality are insufficient amount of the main component, cohering of the particles of the medicine, bad uniformity and so on. Particularly, the mentioned conditions would occur more easily when a product contains two kinds of main components, since there are differences of physical and chemical characteristics as well as ratio of content existing between said two main components. Therefore, a change of the producing process in combining the excipient with the contents of the formula, especially the application in mixture orders and homogenizing methods of the main components with the propellant and other excipients, may generate a pressurized metered dose inhaler with stable, safer and more efficacious qualities.